The function of the heart is to supply the energy required for the circulation of blood in the cardiovascular system. Blood flow through all organs is passive and occurs only because arterial pressure is kept higher than venous pressure by the pumping action of the heart. The right heart pump provides the energy necessary to move blood through the pulmonary vessels and the left heart pump provides the energy that causes flow through the systemic organs.
Venous blood returns from the systemic organs to the right atrium via the superior and inferior venae cavae. It passes through the tricuspid valve into the right ventricle and from there is pumped through the pulmonic valve into the pulmonary circulation via the pulmonary arteries. Oxygenated pulmonary venous blood flows in pulmonary veins to the left atrium and passes through the mitral valve into the left ventricle. From there, it is pumped through the aortic valve into the aorta to be distributed to the systemic organs.
Hence, in its normal operation, the left ventricle of the heart pumps oxygen-rich blood to arteries in the vasculature of the body through the aorta. As the heart pumps, the aortic valve, which is located between the left ventricle and the aorta, opens and closes to control the direction of blood flow. More specifically, during heartbeat or systole, the aortic valve is opened to allow blood to flow from the left ventricle into the aorta. Between heartbeats, or during diastole, however, the aortic valve closes to form a tight seal that prevents blood from leaking back into the ventricle.
The valves are structurally designed to allow flow in only one direction and passively open and close in response to the direction of the pressure differences across them. Typically, the aortic valve is composed of three fibrous leaflets or cusps. The leaflets are forced open against the walls of the aorta during ventricular ejection of blood but fall back during diastole, their free edges coapting to prevent blood from returning into the heart.
The aortic wall behind each aortic valve cusp bulges outward, forming three structures known as sinuses of Valsalva. The two most anterior valvular aortic cusps are known as the left and right coronary cusps because of the origin of the left and right coronary arteries from the respective sinuses of Valsalva and the remaining valvular posterior cusp is known as the non-coronary cusp.
For any of several reasons, it can happen that the aortic valve is somehow damaged and may become stenosed. When this happens, the aortic valve does not open to its normal extent and the flow of blood from the heart into the aorta is hindered. This leads to a heart condition that is commonly known as aortic valve stenosis.
Common etiologies for aortic valve stenosis include congenital abnormality, rheumatic fever or degeneration with calcification in the aging patient. A bicuspid valve is the most common congenital abnormality, and often a raphe in one of the cusps indicates failure of the commissure to develop. Rarely, a unicuspid or quadricuspid valve can be present at birth. Although the bicuspid valve may not be initially stenotic, fibrosis and thickening lead eventually to reduced orifice size with calcification. Indeed, mechanical sheer stress typically leads to calcific injury.
Rheumatic fever scars the leaflet margins, and eventually the commissures fuse and calcify. More than 50% of adults with aortic stenosis are found to have a bicuspid valve, but fibrosis and calcification may make it difficult to determine whether the valve is bicuspid or tricuspid.
In the aging patient with degenerative aortic valve stenosis, calcium deposits usually develop at the sinuses and annulus, whereas the margins of the leaflets often remain free of calcifications.
Currently, there are many proposed theories for the cellular pathophysiology of aortic valve stenosis. Such theories include cardiovascular risk factors initiating a response to injury, mechanical sheer stress, auto-immune phenomena causing degeneration, chronically raised stroke volume and altered calcium metabolism (such as found in renal failure, Paget's disease, etc.).
Regardless of its etiology, aortic stenosis produces an increase in systolic left ventricular pressure. Systolic hypertension in the ventricular chamber is compensated by concentric hypertrophy of the myocardial wall, allowing the wall stress to remain normal. The less compliant, thickened left ventricle becomes more dependent on the atrial contribution to diastolic filling, such that left ventricular performance can deteriorate when atrial contraction is lost, for example during atrial fibrillation or atrial-ventricular dissociation. The abnormal relaxation and increased stiffness of the thickened left ventricle during diastole also result in diastolic dysfunction and elevations of left ventricular and left atrial diastolic pressures.
Myocardial failure can eventually develop from chronic severe valvular obstruction and depression of the contractile state. Left ventricular dilatation can also occur in some patients. Myocardial oxygen consumption remains high owing to elevation of systolic pressure in the left ventricle and increase in left ventricular mass. In addition, the increased left ventricular diastolic pressure reduces the pressure gradient necessary for myocardial perfusion. Thus, significant aortic stenosis creates conditions in which high myocardial oxygen demands are inadequately supported by reduced oxygen supply, which leads to subendocardial ischemia.
Eventually, with a decline in the inotropic state of the myocardium, the ejection fraction is decreased to below the normal range (with or without associated dilatation of the left ventricle). Further elevation of the left ventricular end diastolic pressure (secondary to diastolic dysfunction with or without systolic dysfunction) results in pulmonary venous hypertension. The increased myocardial oxygen demands in aortic stenosis with the underperfused subendocardial myocardium can produce angina pectoris, arrhythmias, and even sudden death.
The development of any of the cardinal symptoms in the setting of severe aortic stenosis indicates substantial mortality risk and is an indication for surgical therapy. The average life expectancy after symptom onset is 2-3 years, less if the symptoms are due to heart failure. Because symptoms, and perhaps sudden death, often accompany physical exertion, vigorous activities and competitive sports should be avoided by patients with aortic stenosis, even if it is only mild to moderate in severity. Hence, aortic stenosis is associated not only with high mortality but also with substantial morbidity.
Calcific aortic stenosis accounts for a large percentage of aortic stenosis cases. The condition is characterized by the build-up of calcified nodules on the upper or superior surface of the aortic valve leaflets. These nodules decrease the flexibility of the leaflets, thereby limiting their mobility and capacity to fully open.
Three techniques have been employed to correct aortic stenosis, namely valve replacement, intra-operative decalcification or debridement or the heart valve and balloon valvuloplasty.
Valve replacement, during open-heart surgery, is currently the standard therapy for symptomatic aortic stenosis. Ten-year survival rates for isolated aortic valve replacement are relatively good, even in elderly patients. However, this technique requires the patient to be healthy enough to undergo sternotomy (chest opening) and open heart surgery. The operative mortality for this procedure, particularly in the elderly, is relatively large.
There are two types of prosthetic heart valves, namely mechanical valves that are composed of only materials that are not derived from living organisms and bio-prosthetic valves that are composed in whole or in part of biological material. Mechanical valves currently in use have a ball-cage construction, a tilted disc construction (1 or 2 discs) or a hinged leaflet construction.
Bio-prosthetic valves generally comprise a supporting stent and a plurality of leaflets. The leaflets are generally composed of biological material, while the stent, when present, generally comprises non-biological material, at least in part. The biological material of the leaflets can be autologous tissues such as pericardium, fascia lata or cardiac valves. Alternatively, this material can be derived from homologous tissue such as non-autologous human tissue for human implantation or can be xenogeneic.
Each type of prosthetic heart valve has advantages and disadvantages. Mechanical heart valves are durable and, hence, more likely to result in long-lasting function but require careful chronic anticoagulation because of thrombo-embolic risk. Chronic anticoagulation therapy, however, carries with it a risk of haemorrhage similar in incidence to that of the residual risk for thrombotic events.
Bio-prosthetic valves initially approximate the haemodynamic properties of the natural valve. They carry a smaller risk of complications secondary to thrombus than do mechanical valves. Such valves, however, carry a significantly higher risk of calcification than mechanical valves. Since treatment of a functionally compromised bio-prosthetic heart valve frequently requires replacement with a new valve (and hence a second open-heart surgery), limitations on the useful life expectancy of a bio-prosthetic heart valve are both a serious medical problem for the patient and a financial drain on the medical system.
Furthermore, all prosthetic heart valves are somewhat stenotic. Prosthetic dysfunction secondary to thrombosis or calcification can lead to increased obstruction or the development of regurgitation. Regurgitation can also result from a perivalvular leak, that is a leak in the area of the sewing ring of the valve. Turbulence associated with valve dysfunction can cause haemolysis and anemia. Even normally functioning prosthetic valves can cause haemolysis in some patients.
Endocarditis is another potential and major complication in patients with prosthetic heart valves. Antibiotic prophylaxis has to be administered prior to dental, gastrointestinal and genito-urinary surgery and other procedures associated with bacteraemia.
Furthermore, some patients have aortic dimensions that are not large enough to easily accommodate conventional replacement valves. Hence, there is a significant number of patients for whom valve replacement is impossible, impractical, or undesirable.
Intra-operative mechanical debridement or decalcification of the aortic valve was used for many years prior to the advent of mechanical replacement valves. In this technique, the aorta is entered surgically but, rather than replace the valve manually, the surgeon removes the calcified deposits, using suitable surgical tools. Recently, ultrasonic debridement has also been demonstrated to be effective to remove calcific deposits. Nevertheless, this technique still requires the patient to be healthy enough to survive and recuperate from thoracic surgery, and involves all the costs and risks attendant with such surgery.
A third technique for correcting aortic stenosis involves percutaneous balloon aortic valvuloplasty. In this procedure, an inflatable balloon catheter is advanced to the aortic valve and inflated to compress and fracture the calcified nodules in an attempt to increase leaflet mobility. Although this procedure eliminates many of the risks and disadvantages attendant with the preceding two techniques, re-stenosis is very common within one year, limiting the usefulness of the technique to temporarily mitigating symptoms for those patients who are poor surgical candidates or refuse surgery.
Hence, there exists a need for a non-surgical treatment of aortic valve stenosis and other valvular diseases.
The present invention differs significantly from the prior art and current trends by providing a method for not only preventing the progression of aortic stenosis but also for reducing the degree of stenosis using a reverse lipid transport agonist.
An object of the present invention is therefore to provide a novel non-surgical treatment of valvular disease.